Once at the plasma membrane, peptide-loaded MHC-II (pMHC-II) complexes are displayed for recognition by CD4 T cells. T cells are exquisitely sensitive and are capable of recognizing very small amounts of pMHC-II. We first reported that pMHC-II is constitutively associated with plasma membrane microdomains, termed lipid rafts, and that raft association increases the local density of pMHC-II to support T cell activation by small numbers of pMHC-II complexes. We have been following the kinetics of pMHC-II complex formation in living cells from their initial site of formation in intracellular antigen processing compartments until their movement and deposition in the plasma membrane of dendritic cells. We have found that newly-generated pMHC-II complexes first arrive at the plasma membrane in small microclusters that remain stable over time. These microclusters are stabilized by cholesterol/lipid interactions, as perturbing cholesterol levels disrups these pMHC-II microclusters. Our current goal is to identify the molecular signals that regulate pMHC-II association with lipid membrane domains.